TNFα has been demonstrated to be involved in infectious diseases, immune disorders, autoimmune pathologies, graft vs host disease (GVHD), neoplasia/cancer and cancer-associated cachexia. See, Feldman M., 2002 Nat. Rev. Immunol., 2:364. In particular, TNFα levels are dramatically induced in gram negative sepsis, endotoxic shock (See, Michie et al., 1989 Br. J. Surg. 76:670) Crohn's disease, and rheumatoid arthritis. The implications of TNFα in such a wide variety of indications highlights the importance of developing specific biological therapeutics targeting this inflammatory cytokine.
Several investigators report the characterization of monoclonal antibodies against TNFα which neutralize its activity in vitro. See, Liang C M, et al., 1986, Biochem. Biophys Res. Commun., 137:847, and Meager A, et al., 1987 Hybridoma 6:305. Some of these antibodies were used to map epitopes of human TNFα and develop enzyme immunoassays and to assist in the purification of recombinant TNFα. See Fendly B M, et al., 1987 Hybridoma, 6:359; Hirai M, et al., 1987 J. Immunol Methods, 96:57; Moller A, et al., 1990 Cytokine, 2:162; Bringman T S and Aggarwal B B, 1987, Hybridoma, 6:489. Unfortunately, the antibodies generated for these studies would not be useful as therapeutic neutralizing TNFα antibodies for treating human patients since they were derived from non-human species and lack specificity for TNFα.
Neutralizing antisera or mAbs to TNFα have shown efficacy in non-human mammals by abrogating adverse pathophysiological events and preventing death after lethal challenge in experimental endotoxemia. These effects have been demonstrated in rodent and non-human primate model systems. See, Beutler B, et al., 1985 Science, 229:869; Tracey K J, et al., 1987 Nature, 330:662; Mathison J C, et al., 1988 J. Clin. Invest., 81:1925; Shimamoto Y, et al., 1988, Immunol. Lett., 17:311; Opal S M, et al., 1990, J. Infect. Dis., 161:1148; Silva A T, et al., 1990, J. Infect. Dis., 162:454; Hinshaw L B, et al., 1990, Circ. Shock, 30:279.
Various forms of neutralizing antibodies currently exist and are reviewed by Feldman. See, Feldman M, 2002, Nat. Rev. Immunol., 2:364. As described in this review, a great deal of effort has been expended to create a neutralizing antibody that would yield a therapeutically suitable antibody for chronic administration to humans. Currently, antibody/TNFR fusion (fcIg/TNFR) proteins (Enbrel) have shown some utility, but are challenged by a short half-life in the serum leading to frequent administration (e.g., twice weekly) of the drug. A neutralizing therapeutic antibody to TNFα for chronic treatment would exceed the half-life issue (one injection per 3-4 weeks) as long as the antibody itself was not immunogenic. Others have attempted to create neutralizing antibodies to TNFα which have the desired characteristics of low/no immunogenicity and a half life typical of their endogenous counterparts without success. Examples of such antibodies include mouse/human chimeras, such as Infliximab (cA2 or Remicade), and the humanized antibody CDP571 or Adalimumab (D2E7 or Humira). These represent attempts to create neutralizing therapeutic antibodies which closely resemble their human counterparts.
Unfortunately, the full potential of these drugs may not be realized due to their inherent potential immunogenicity, compromised half-life and/or reduced avidity/affinity for TNFα. Host immune responses induced by these chimeric antibodies can lead to clearance of the antibodies from the circulation and make repeated administration unsuitable for therapy due to loss of efficacy. These problems ultimately reduce the therapeutic benefit to the patient. Additional problems in scale-up and manufacturing may also be encountered using antibodies or fragments thereof, such as those mentioned above.
Thus, for the above reasons, there exists a need in the art to provide an alternative to patients in clinically indicated populations where TNFα is responsible for the pathophysiology of a particular disease. Fully human, high affinity, neutralizing monoclonal antibodies, or fragments thereof, for chronic administration provide the desired characteristics of a non-immunogenic therapeutic option with a half-life suitable for less frequent administration.